Altered lipid profiles in the stratum corneum of Sjögren-Larsson syndrome

Nakajima, Kimiko; Sano, Shigetoshi; Uchida, Yoshikazu; Akiyama, Masashi; Morita, Yukari; Shimizu, Hiroshi

doi:10.1016/j.jdermsci.2011.03.009

Cited by 12 publications

(14 citation statements)

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“…Aldh3a2 KO Mice Exhibit Delayed Skin Barrier Recovery-In SLS patients, some ceramide species such as acylceramide EOS are reduced (10). Therefore, we examined ceramide/acylceramide levels in the epidermis of Aldh3a2 Ϫ/Ϫ mice by LC/MS/MS analysis.…”

Section: Greatly Decreased In Aldh3a2mentioning

confidence: 99%

Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier Recovery

Naganuma

Takagi

Kanetake

et al. 2016

Journal of Biological Chemistry

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The fatty aldehyde dehydrogenase (FALDH) ALDH3A2 is the causative gene of Sjögren Larsson syndrome (SLS Sjögren-Larsson syndrome (SLS)2 is a hereditary neurocutaneous disorder caused by mutations in the fatty aldehyde dehydrogenase (FALDH) gene, ALDH3A2. The major symptoms of SLS are mental retardation, spastic di-or tetraplegia, and ichthyosis, with crystalline macular dystrophy sometimes comorbid (1). ALDH3A2 catalyzes the conversion of fatty aldehydes with medium-chain (MC) to very-long-chain fatty acids (FA) (MC, C5-C10; long-chain (LC), C11-C20; and very-longchain, ՆC21), with the most preferred substrates being C16 and C18 aldehydes (2, 3). To date, more than 70 mutations have been found in the ALDH3A2 gene of SLS patients, and most of them cause Ͼ90% reduction in enzyme activity (4). Because aldehyde molecules are reactive and toxic in general, it is considered that accumulated fatty aldehydes cause the SLS pathology by reacting with certain important proteins in the nervous system and epidermis and compromising their functions. Furthermore, the literature lacks a detailed description of the characteristics of Aldh3a2 knock-out mice.The skin symptom ichthyosis is characterized by dry, thickened, and scaly skin, often likened to fish scales, and is caused by a skin permeability barrier defect related to multilayered lipids (lipid lamellae) in the epidermis. The epidermis is composed of four cell layers, the stratum basale, stratum spinosum, stratum granulosum, and the stratum corneum, the last of which is the site of these lipid lamellae, and accordingly has the most important role in skin barrier formation (5, 6). Keratinocytes proliferate in the stratum basale and migrate outward, differentiating into cell layer-specific cell types. The major lipid components of lipid lamellae are ceramides, cholesterol, and FAs, with ceramides being the most abundant (5, 6). A variety of ceramide species exist in the epidermis. Among them, acylceramides are a class of epidermis-specific ceramides that play an essential role in skin barrier formation (7,8). Ceramides are normally composed of a long-chain base (LCB) and a FA (9). However, acylceramides contain an additional hydrophobic chain (linoleic acid), which is esterified with the hydroxylated -carbon of the FA. In the epidermis of SLS patients, some ceramide species, including the acylceramide EOS (a combination of an esterified -hydroxy FA and the LCB sphingosine), are greatly reduced (10).Several metabolic pathways generate the substrates of ALDH3A2, fatty aldehydes. These include metabolic pathways of leukotriene B 4 , diet-derived phytol, plasmalogens, and fatty alcohols (11)(12)(13)(14)(15). Furthermore, we recently revealed that metabolism of LCBs also generates fatty aldehydes, i.e. hexadecanal (C16:0 aldehyde) from dihydrosphingosine (DHS) and

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Section: Greatly Decreased In Aldh3a2mentioning

confidence: 99%

Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier Recovery

Naganuma

Takagi

Kanetake

et al. 2016

Journal of Biological Chemistry

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“…Cutaneous scales from SLS patients have reduced levels of ceramide-1 (acylceramide) and ceramide-6 [152, 153]. Acylceramide is uniquely found in skin and is critically important for cutaneous integrity and the water barrier [52].…”

Section: Biochemical Pathogenesis Of Epidermal Dysfunction In Slsmentioning

confidence: 99%

“…The oxidation of fatty aldehyde by FALDH should contribute in part to the fatty acid pool in the skin, although its relative contribution compared to phospholipid hydrolysis is probably small. The total free fatty acid content of cutaneous scales from one SLS patient was reported as normal [153] but it is, nevertheless, possible that a critical fatty acid product of FALDH activity is not produced in SLS skin.…”

Section: Biochemical Pathogenesis Of Epidermal Dysfunction In Slsmentioning

confidence: 99%

Fatty aldehyde and fatty alcohol metabolism: Review and importance for epidermal structure and function

Rizzo

2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

101

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Normal fatty aldehyde and alcohol metabolism is essential for epidermal differentiation and function. Long-chain aldehydes are produced by catabolism of several lipids including fatty alcohols, sphingolipids, ether glycerolipids, isoprenoid alcohols and certain aliphatic lipids that undergo α- or ω-oxidation. The fatty aldehyde generated by these pathways is chiefly metabolized to fatty acid by fatty aldehyde dehydrogenase (FALDH, alternately known as ALDH3A2), which also functions to oxidize fatty alcohols as a component of the fatty alcohol:NAD oxidoreductase (FAO) enzyme complex. Genetic deficiency of FALDH/FAO in patients with Sjögren-Larsson syndrome (SLS) results in accumulation of fatty aldehydes, fatty alcohols and related lipids (ether glycerolipids, wax esters) in cultured keratinocytes. These biochemical changes are associated with abnormalities in formation of lamellar bodies in the stratum granulosum and impaired delivery of their precursor membranes to the stratum corneum (SC). The defective extracellular SC membranes are responsible for a leaky epidermal water barrier and ichthyosis. Although lamellar bodies appear to be the pathogenic target for abnormal fatty aldehyde/alcohol metabolism in SLS, the precise biochemical mechanisms are yet to be elucidated. Nevertheless, studies in SLS highlight the critical importance of FALDH and normal fatty aldehyde/alcohol metabolism for epidermal function.

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“…Two reports have identified a reduction in ceramide-1 (1- O -acyl-ceramide) in cutaneous scales for SLS patients. [79,80] Ceramide-1 is unique to the skin and structurally differs from most other ceramides by incorporating linoleic acid in acyl linkage with the ω-carbon of the very long-chain fatty acid portion of ceramide. [81] Nutritional linoleic acid deficiency is associated with a defective epidermal water barrier and cutaneous desquamation, which is thought to be because of reduced acyl-ceramide.…”

Section: Pathogenic Mechanismsmentioning

confidence: 99%

Genetics and prospective therapeutic targets for Sjögren-Larsson Syndrome

Rizzo

2016

Expert Opinion on Orphan Drugs

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Introduction Sjögren-Larsson syndrome (SLS) is a rare neurocutaneous disease characterized by ichthyosis, spasticity, intellectual disability and a distinctive retinopathy. It is caused by inactivating mutations in ALDH3A2, which codes for fatty aldehyde dehydrogenase (FALDH) and results in abnormal metabolism of long-chain aliphatic aldehydes and alcohols. The potential disease mechanisms leading to symptoms include 1) accumulation of toxic fatty aldehydes that form covalent adducts with lipids and membrane proteins; 2) physical disruption of multi-lamellar membranes in skin and brain; 3) abnormal activation of the JNK cell signaling pathway; and 4) defective farnesol metabolism resulting in abnormal PPAR-α dependent gene expression. Currently, no effective pathogenesis-based therapy is available. Areas Covered The clinical, pathologic and genetic features of SLS are summarized. The biochemical abnormalities caused by deficient activity of FALDH are reviewed in the context of proposed pathogenic mechanisms and potential therapeutic interventions. Expert Opinion The most promising pharmacologic approach to SLS involves blocking the formation of potentially harmful fatty aldehyde adducts using aldehyde scavenging drugs, currently in phase 2 clinical trials. Other approaches needing further investigation include: 1) ALDH-specific activator drugs and PPAR-α agonists to increase mutant FALDH activity; 2) inhibitors of the JNK phosphorylation cascade; 3) antioxidants to decrease aldehyde load; 4) dietary lipid modification; and 5) gene therapy.

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Altered lipid profiles in the stratum corneum of Sjögren-Larsson syndrome

Cited by 12 publications

References 10 publications

Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier Recovery

Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier Recovery

Fatty aldehyde and fatty alcohol metabolism: Review and importance for epidermal structure and function

Genetics and prospective therapeutic targets for Sjögren-Larsson Syndrome

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